WO2015116537A1 - Analogues de téicoplanine et leurs utilisations - Google Patents

Analogues de téicoplanine et leurs utilisations Download PDF

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WO2015116537A1
WO2015116537A1 PCT/US2015/012914 US2015012914W WO2015116537A1 WO 2015116537 A1 WO2015116537 A1 WO 2015116537A1 US 2015012914 W US2015012914 W US 2015012914W WO 2015116537 A1 WO2015116537 A1 WO 2015116537A1
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optionally substituted
alkyl
compound
certain embodiments
coa
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PCT/US2015/012914
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WO2015116537A9 (fr
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Tsung-Lin Li
Syue-Yi Lyu
Yu-Chen Liu
Chin-Yuan Chang
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Academia Sinica
Liang, Chi-Ming
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Priority to EP15743950.6A priority Critical patent/EP3099703A4/fr
Priority to US15/115,179 priority patent/US10316064B2/en
Priority to CN201580006333.8A priority patent/CN106132980A/zh
Publication of WO2015116537A1 publication Critical patent/WO2015116537A1/fr
Publication of WO2015116537A9 publication Critical patent/WO2015116537A9/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K9/00—Peptides having up to 20 amino acids, containing saccharide radicals and having a fully defined sequence; Derivatives thereof
    • C07K9/006—Peptides having up to 20 amino acids, containing saccharide radicals and having a fully defined sequence; Derivatives thereof the peptide sequence being part of a ring structure
    • C07K9/008—Peptides having up to 20 amino acids, containing saccharide radicals and having a fully defined sequence; Derivatives thereof the peptide sequence being part of a ring structure directly attached to a hetero atom of the saccharide radical, e.g. actaplanin, avoparcin, ristomycin, vancomycin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
    • C12P19/00—Preparation of compounds containing saccharide radicals
    • C12P19/44—Preparation of O-glycosides, e.g. glucosides
    • C12P19/60—Preparation of O-glycosides, e.g. glucosides having an oxygen of the saccharide radical directly bound to a non-saccharide heterocyclic ring or a condensed ring system containing a non-saccharide heterocyclic ring, e.g. coumermycin, novobiocin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • Teicoplanin is a glycopeptide antibiotic that has bactericidal activity against Gram positive aerobic and anaerobic bacteria. It inhibits the growth of susceptible organisms by interfering with the biosynthesis of the cell- wall at a site different from that affected by beta-lactam antibiotics. Teicoplanin is a mixture of glycopeptide components which, on the basis of high performance liquid chromatography (HPLC) separation, are currently classified into six main subcomponents (as individual or as a group) according to their alkyl side chain and therefore by their polarity in elution in the referenced chromatographic system.
  • HPLC high performance liquid chromatography
  • Bacteria have the ability to generate resistance to antibiotics through lateral gene transfer, mutation of enzymes, or the expression of enzymes which actively pump the antibiotic out of the cell or break it down. Over the past 10 years, resistance to existing antibiotics has become a significant problem. In practice, strains such as methicillin- resistant Staphylococcus Aureus (MRSA), methicillin-resistant Staphylococcus
  • Glycopeptide is generally the last line antibiotic to treat multidrug-resistant gram-positive pathogens MRSA and VRE.
  • This class of antibiotics is empowered by the N-acyltransferase, attaching a long aliphatic chain on the glucosamine moiety at the central residue of glycopeptide pseudoaglycone.
  • the present invention provides compounds of Formula (I) and pharmaceutical compositions thereof, which are useful in inhibiting bacterial growth (e.g. Gram positive aerobic and anaerobic bacteria).
  • the present invention further provides methods of using the compounds described herein, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, and pharmaceutical compositions thereof, to inhibit bacterial growth.
  • the present invention further provides methods of using the compounds described herein, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, and pharmaceutical compositions thereof, to treat or prevent bacterial infections.
  • this invention features compounds of the following formula:
  • X is of Formula (i):
  • Y is hydrogen or of Formula (ii):
  • Z is of Formula (iii):
  • each instance of R is independently optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, or -OR°;
  • each instance of R° is independently hydrogen, optionally substituted alkyl, or an oxygen protecting group
  • each of R p and R q is independently hydrogen, optionally substituted Ci_6 alkyl, an optionally substituted carbohydrate, or an oxygen protecting group;
  • n is 0 or an integer of 1 to 15, inclusive
  • n is 0 or an integer of 1 to 15, inclusive
  • a provided compound is of Formula (I- a):
  • a provided compound is of Formula (I-b):
  • R p is hydrogen, optionally substituted Ci_ 6 alkyl, an optionally substituted carbohydrate, or an oxygen protecting group.
  • R p is hydrogen. In certain embodiments, R p is optionally substituted Ci_ 6 alkyl, an optionally substituted carbohydrate, or an oxygen protecting group.
  • R q is hydrogen, optionally substituted C ⁇ alkyl, an optionally substituted carbohydrate, or an oxygen protecting group.
  • R q is hydrogen. In certain embodiments, R q is optionally substituted Ci_ 6 alkyl, an optionally substituted carbohydrate, or an oxygen protecting group.
  • Ri is optionally substituted alkyl. In certain embodiments, Ri is optionally substituted alkyl. In certain embodiments, Ri is optionally substituted alkyl. In certain
  • Ri is optionally substituted CM S alkyl. In certain embodiments, Ri is optionally substituted Ci_io alkyl. In certain embodiments, Ri is optionally substituted Ci_ 6 alkyl. In certain embodiments, Ri is substituted alkyl. In certain embodiments, Ri is substituted C 1-15 alkyl. In certain embodiments, Ri is optionally substituted C 1-15 alkylaryl, substituted C MS alkylalkynyl, or optionally substituted C 1-15 alkylhydroxyl.
  • Ri is substituted Ci_io alkyl. In certain embodiments, Ri is substituted Ci_ 6 alkyl. In certain embodiments, Ri is unsubstituted alkyl. In certain embodiments, Ri is unsubstituted C 1-15 alkyl. In certain embodiments, Ri is unsubstituted Ci-io alkyl. In certain embodiments, Ri is unsubstituted C 1-6 alkyl.
  • Ri is optionally substituted alkenyl. In some embodiments, Ri is optionally substituted C 2-15 alkenyl. In some embodiments, Ri is optionally substituted C 2-10 alkenyl. In some embodiments, Ri is substituted C 2-15 alkenyl. In some embodiments, Ri is substituted C 2 - 10 alkenyl. In some embodiments, Ri is unsubstituted C 2 _i5 alkenyl. In some embodiments, Ri is unsubstituted C 2-1 o alkenyl.
  • Ri is optionally substituted alkynyl. In some embodiments, Ri is optionally substituted C 2 _i 5 alkynyl. In some embodiments, Ri is optionally sub stituted C 2 _ i o alkynyl .
  • Ri is optionally substituted 3- to 6- membered heterocyclyl. In some embodiments, Ri is optionally substituted 6-membered heterocyclyl with one heteroatom selected from the group consisting of N, O, and S. In some embodiments, Ri is optionally substituted 6- membered heterocyclyl with two heteroatoms each independently selected from the group consisting of N, O, and S. In some embodiments, Ri is optionally substituted 6-membered heterocyclyl with three heteroatoms each independently selected from the group consisting of N, O, and S. In some embodiments, Ri is optionally substituted 5-membered heterocyclyl with one heteroatom selected from the group consisting of N, O, and S.
  • Ri is optionally substituted 5-membered heterocyclyl with two heteroatoms each independently selected from the group consisting of N, O, and S. In some embodiments, Ri is optionally substituted aryl. In some embodiments, Ri is optionally substituted phenyl. In some embodiments, Ri is phenyl. In some embodiments, Ri is optionally substituted heteroaryl. In some embodiments, Ri is optionally substituted 6-membered heteroaryl with one heteroatom selected from the group consisting of N, O, and S. In some embodiments, Ri is optionally substituted 6-membered heteroaryl with two heteroatoms each independently selected from the group consisting of N, O, and S.
  • Ri is optionally substituted 5-membered heteroaryl with one heteroatom selected from the group consisting of N, O, and S. In some embodiments, Ri is optionally substituted 5-membered heteroaryl with two heteroatoms each independently selected from the group consisting of N, O, and S.
  • heterocyclyl optionally substituted aryl, optionally substituted heteroaryl, or OR°;
  • each instance of R° is independently hydrogen, optionally substituted alkyl, or an oxygen protecting group.
  • R c is OR°; and R° is optionally substituted Ci_ 6 alkyl.
  • R 2 is optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted c c
  • R 2 is optionally substituted alkyl. In certain embodiments, R 2 is optionally substituted C 1-15 alkyl. In certain embodiments, R 2 is optionally substituted C 1-10 alkyl. In certain embodiments, R 2 is optionally substituted Ci_6 alkyl. In certain embodiments, R 2 is substituted alkyl. In certain embodiments, R 2 is substituted C 1-15 alkyl. In some embodiments, R 2 is optionally substituted C 1-15 alkylaryl, substituted C 1-15 alkylalkynyl, or optionally substituted C 1-15 alkylhydroxyl.
  • R 2 is substituted C 1-10 alkyl. In certain embodiments, R 2 is substituted Ci_6 alkyl. In certain embodiments, R 2 is unsubstituted alkyl. In certain embodiments, R 2 is unsubstituted C 1-15 alkyl. In certain embodiments, R 2 is unsubstituted Ci-w alkyl. In certain embodiments, R 2 is unsubstituted Ci_6 alkyl.
  • R 2 is optionally substituted alkenyl. In some embodiments, R 2 is optionally substituted C 2-15 alkenyl. In some embodiments, R 2 is optionally substituted C 2-1 o alkenyl. In some embodiments, R 2 is substituted C 2-15 alkenyl. In some embodiments, R 2 is substituted C 2-1 o alkenyl. In some embodiments, R 2 is unsubstituted C 2-1 5 alkenyl. In some embodiments, R 2 is unsubstituted C 2-1 o alkenyl.
  • R 2 is optionally substituted alkynyl. In some embodiments, R 2 is optionally substituted C 2-15 alkynyl. In some embodiments, R 2 is optionally substituted C 2-1 o alkynyl.
  • R 2 is optionally substituted 3- to 6- membered heterocyclyl. In some embodiments, R 2 is optionally substituted 6-membered heterocyclyl with one heteroatom selected from the group consisting of N, O, and S. In some embodiments, R 2 is optionally substituted 6- membered heterocyclyl with two heteroatoms each independently selected from the group consisting of N, O, and S. In some embodiments, R 2 is optionally substituted 6-membered heterocyclyl with three heteroatoms each independently selected from the group consisting of N, O, and S. In some embodiments, R 2 is optionally substituted 5-membered heterocyclyl with one heteroatom selected from the group consisting of N, O, and S.
  • R 2 is optionally substituted 5-membered heterocyclyl with two heteroatoms each independently selected from the group consisting of N, O, and S. In some embodiments, R 2 is optionally substituted aryl. In some embodiments, R 2 is optionally substituted phenyl. In some embodiments, R 2 is phenyl. In some embodiments, R 2 is optionally substituted heteroaryl. In some embodiments, R 2 is optionally substituted 6-membered heteroaryl with one heteroatom selected from the group consisting of N, O, and S. In some embodiments, R 2 is optionally substituted 6-membered heteroaryl with two heteroatoms each independently selected from the group consisting of N, O, and S.
  • R 2 is optionally substituted 5-membered heteroaryl with one heteroatom selected from the group consisting of N, O, and S. In some embodiments, R 2 is optionally substituted 5-membered heteroaryl with two heteroatoms each independently selected from the group consisting of N, O, and S.
  • heterocyclyl optionally substituted aryl, optionally substituted heteroaryl, or OR°;
  • R° is independently hydrogen, optionally substituted alkyl, or an oxygen protecting group.
  • R c is OR°; and R° is optionally substituted C 1-6 alkyl.
  • R 2 is one of the following formulae:
  • m is 0 or an integer of 1 to 15, inclusive. In certain embodiments, m is 0. In certain embodiments, m is an integer of 1 to 15, inclusive. In certain embodiments, m is an integer of 5 to 15, inclusive. In certain embodiments, m is an integer of 5 to 10, inclusive. In certain embodiments, m is an integer of 10 to 15, inclusive. In certain embodiments, m is an integer of 1 to 10, inclusive. In certain embodiments, m is an integer of 1 to 5, inclusive.
  • n is 0 or an integer of 1 to 15, inclusive. In certain embodiments, n is 0. In certain embodiments, n is an integer of 1 to 15, inclusive. In certain embodiments, n is an integer of 5 to 15, inclusive. In certain embodiments, n is an integer of 5 to 10, inclusive. In certain embodiments, n is an integer of 10 to 15, inclusive. In certain embodiments, n is an integer of 1 to 10, inclusive. In certain embodiments, n is an integer of 1 to 5, inclusive.
  • Y is hydrogen or of Formula (ii): (ii). In certain embodiments, Y is hydrogen. In certain embodiments, Y is hydrogen or of
  • Formula is of one of the following formulae:
  • Z is of Formula (
  • a derivative of Formula (iii) refers to a compound with one or more suitable substitutions (e.g., protecting groups) on any hydrogen, and/or any functional group (e.g., hydroxyl, amino, and/or carboxylic acid groups) in Formula (iii).
  • suitable substitutions e.g., protecting groups
  • any functional group e.g., hydroxyl, amino, and/or carboxylic acid groups
  • Hydroxyl and carboxylic acid protecting groups are well known in the art and include those described in detail in Protecting Groups in Organic Synthesis, T. W.
  • each instance of R ⁇ is, independently, selected from Ci-w alkyl, C ⁇ o perhaloalkyl, C 2 _io alkenyl, C 2 _io alkynyl, C ⁇ o heteroalkyl, C 2 _io heteroalkenyl, C 2 10 heteroalkynyl, C 3 _io carbocyclyl, 3-14 membered heterocyclyl, C 6 -i4 aryl, and 5-14 membered heteroaryl, or two R ⁇ groups are joined to form a 3-14 membered
  • a provided compound is one of the compounds in Table
  • Another aspect of the present invention provides a method of preparing a teicoplanin analog, comprising incubating a mixture comprising a long-chain acyltransferase, an acyl- acceptor, and an acyl-donor under suitable conditions allowing for occurrence of the enzymatic reaction catalyzed by the long-chain acyltransferase to produce the teicoplanin analog,
  • the acyl-acceptor is of Formula (I-c)
  • each instance of R is independently optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, or -OR°;
  • each instance of R° is independently hydrogen, optionally substituted alkyl, or an oxygen protecting group
  • each of R p and R q is independently hydrogen, optionally substituted Ci_6 alkyl, an optionally substituted carbohydrate, or an oxygen protecting group; and each of ml and m2 is independently 0 or an integer of 1 to 15, inclusive.
  • the acyl-donor is of Formula (iii) and the mixture further comprises free CoA.
  • the mixture has a pH of about 6 to about 10. In certain embodiments, the mixture has a pH of about 8 to about 10. In certain embodiments, the mixture has a pH of about 6 to about 8.
  • acyltransferase refers to a type of transferase enzyme that catalyze the transfer of an acyl group from one substance to another.
  • the acyltransferase is a long-chain-alcohol O-fatty-acyltransferase that catalyzes the chemical reaction:
  • the acyltransferase is a long-chain-amino acyltransferase that catalyzes the chemical reaction:
  • long-chain alcohols or named fatty alcohols or long-chain amines (or named fatty amines) are usually high-molecular- weight aliphatic alcohols or high- molecular-weight aliphatic amines.
  • the "long chain” refers to an aliphatic chain having over six carbons. In certain embodiments, the long chain has over eight carbons. In certain embodiments, the long chain has over ten carbons. In certain embodiments, the long chain has over twelve carbons. In certain embodiments, the long chain has over fourteen carbons. In certain embodiments, the long chain has over sixteen carbons.
  • the long-chain acyltransferase is N-acyl transferase. In certain embodiments, the long-chain acyltransferase is Orfllb or DBv8. In certain embodiments, the long-chain acyltransferase is Orfllb. In certain embodiments, the long- chain acyltransferase is DBv8.
  • Orfllb or DBv8 includes both wide type and derivative proteins obtained from Orfllb or DBv8 genes.
  • Orfllb or DBv8 encompasses mutants having amino acid sequences by substitution of one or more amino acids in the wide types for one or more different amino acids. The mutation can be conservative mutations or point mutations.
  • the acyltransferase includes one, two, three, four, or five point mutations. In certain embodiments, these point mutations may be conservative changes (e.g., mutation of a serine to a threonine). In certain embodiments, the acyltransferase includes one, two, three, four, five, or more additional amino acids. In certain embodiments, the acyltransferase has one, two, three, four, or five amino acids removed from the sequence. In certain embodiments, the resulting amino acid sequence is at least 90%, at least 95%, at least 97%, at least 98%, or at least 99% homologous or identical to the wild type sequence.
  • new single uniform teicoplanin analogs e.g. 2-acylated teicoplanin analogs
  • double acylated teicoplanin analogs 2,6-diacylted teicoplanin analogs
  • the provided methods use the natural teicoplanin mixtures and acyl-CoAs/acyl-NAC, and optionally free CoA, as the substrates under catalysis of Orfllb or DBv8 to generate new single uniform teicoplanin analogs (e.g. 2-acylated teicoplanin analogs) or double acylated teicoplanin analogs (2-, 6- diacylted teicoplanin analogs) in a one-step reaction.
  • new single uniform teicoplanin analogs e.g. 2-acylated teicoplanin analogs
  • double acylated teicoplanin analogs 2, 6- diacylted teicoplanin analogs
  • the provided methods use the natural teicoplanin mixtures and acyl-CoAs, and optionally free CoA, as the substrates under catalysis of Orfllb or DBv8 to generate new single uniform teicoplanin analogs (e.g. 2-acylated teicoplanin analogs) or double acylated teicoplanin analogs (2-,6-diacylted teicoplanin analogs) in a one-step reaction.
  • new single uniform teicoplanin analogs e.g. 2-acylated teicoplanin analogs
  • double acylated teicoplanin analogs 2,6-diacylted teicoplanin analogs
  • the provided methods use the natural teicoplanin mixtures and acyl-NAC, and optionally free CoA, as the substrates under catalysis of Orfllb or DBv8 to generate new single uniform teicoplanin analogs (e.g. 2-acylated teicoplanin analogs) or double acylated teicoplanin analogs (2-,6-diacylted teicoplanin analogs) in a one-step reaction.
  • the provided method is carried out at a pH of about 6.0 to 8.0 to generate a mono-acylated teicoplanin analog (e.g. Compound 9).
  • the provided method is carried out at a pH of about 8.0 to 10.0 (e.g. pH of 9.0) to generate a diacylated teicoplanin analog (e.g. Compound 11).
  • the provided synthetic methods avoid the tedious preparation/purification of teicoplanin precursors such as teicoplanin aglycon or teicoplanin pseudoaglycone as shown in the art, for example, Kruger, R. G. et al. Tailoring of glycopeptide scaffolds by the acyltransferases from the teicoplanin and A- 40,926 biosynthetic operons. Chem Biol 12, 131-140,doi: 10.1016/j.chembiol.2004.12.005 (2005); Kahne, D., Leimkuhler, C, Lu, W. & Walsh, C. Glycopeptide and
  • R lp is optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted
  • R lp is optionally substituted alkyl. In certain embodiments, R lp is optionally substituted C 1-15 alkyl. In certain embodiments, R lp is optionally substituted C 1-15 alkylaryl, substituted Ci_ is alkylalkynyl, or optionally substituted C 1-15 alkylhydroxyl. In certain embodiments, R lp is optionally substituted Ci-w alkyl. In certain embodiments, R lp is optionally substituted Ci_6 alkyl. In certain embodiments, R lp is substituted alkyl. In certain embodiments, R lp is substituted C 1-15 alkyl.
  • R lp is substituted C 1-10 alkyl. In certain embodiments, R lp is substituted C 1-6 alkyl. In certain embodiments, R lp is unsubstituted alkyl. In certain embodiments, R lp is unsubstituted C 1-15 alkyl. In certain embodiments, R lp is unsubstituted C 1-10 alkyl. In certain embodiments, R lp is unsubstituted Ci_6 alkyl.
  • R lp is optionally substituted alkenyl. In some embodiments, R lp is optionally substituted C 2-15 alkenyl. In some embodiments, R lp is optionally substituted C 2 - 10 alkenyl. In some embodiments, R lp is substituted C 2-15 alkenyl. In some embodiments, R lp is substituted C 2-1 o alkenyl. In some embodiments, R lp is unsubstituted C 2-1 5 alkenyl. In some embodiments, R lp is unsubstituted C 2-1 o alkenyl.
  • R lp is optionally substituted alkynyl. In some embodiments, R lp is optionally substituted C 2-15 alkynyl.
  • R lp is optionally substituted C 2-1 o alkynyl. In some embodiments, R lp is optionally substituted carbocyclyl, optionally substituted
  • R lp is optionally substituted C 3 _ 6 carbocyclyl, optionally
  • R lp is optionally substituted carbocyclyl. In some embodiments, R lp is optionally substituted C 3 _ 6 carbocyclyl. In some embodiments, R lp is optionally substituted heterocyclyl. In some embodiments, R lp is optionally substituted 3- to 6- membered heterocyclyl. In some embodiments, R lp is optionally substituted 6-membered heterocyclyl with one heteroatom selected from the group consisting of N, O, and S.
  • R lp is optionally substituted 6- membered heterocyclyl with two heteroatoms each independently selected from the group consisting of N, O, and S. In some embodiments, R lp is optionally substituted 6- membered heterocyclyl with three heteroatoms each independently selected from the group consisting of N, O, and S. In some embodiments, R lp is optionally substituted 5- membered heterocyclyl with one heteroatom selected from the group consisting of N, O, and S. In some embodiments, R lp is optionally substituted 5-membered heterocyclyl with two heteroatoms each independently selected from the group consisting of N, O, and S. In some embodiments, R lp is optionally substituted aryl.
  • R lp is optionally substituted phenyl. In some embodiments, R lp is phenyl. In some embodiments, R lp is optionally substituted heteroaryl. In some embodiments, R lp is optionally
  • R lp is optionally substituted 6-membered heteroaryl with one heteroatom selected from the group consisting of N, O, and S.
  • R lp is optionally substituted 6- membered heteroaryl with two heteroatoms each independently selected from the group consisting of N, O, and S.
  • R lp is optionally substituted 5- membered heteroaryl with one heteroatom selected from the group consisting of N, O, and S.
  • R lp is optionally substituted 5-membered heteroaryl with two heteroatoms each independently selected from the group consisting of N, O, and S.
  • heterocyclyl optionally substituted aryl, optionally substituted heteroaryl, or OR°;
  • R° is independently hydrogen, optionally substituted alkyl, or an oxygen protecting group.
  • R c is OR°; and R° is independently hydrogen, optionally substituted alkyl, or an oxygen protecting group.
  • R c is OR°; and R° is optionally substituted C 1-6 alkyl.
  • R lp is of one of the following formulae:
  • R lc is optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted
  • R lc is optionally substituted alkyl. In certain embodiments, R lc is optionally substituted C 1-15 alkyl.
  • R lc is optionally substituted C 1-15 alkylaryl, substituted C 1-15 alkylalkynyl, or optionally substituted C 1-15 alkylhydroxyl. In certain embodiments, R lc is optionally substituted C 1-10 alkyl. In certain embodiments, R lc is optionally substituted C 1-6 alkyl. In certain embodiments, R lc is substituted alkyl. In certain embodiments, R lc is substituted C 1-15 alkyl. In certain embodiments, R lc is substituted Ci- io alkyl. In certain embodiments, R lc is substituted Ci_6 alkyl. In certain embodiments, R lc is unsubstituted alkyl. In certain embodiments, R lc is unsubstituted C 1-15 alkyl. In certain embodiments, R lc is unsubstituted Ci-w alkyl. In certain embodiments, R lc is
  • R lc is optionally substituted alkenyl. In some embodiments, R lc is optionally substituted C 2-15 alkenyl. In some embodiments, R lc is optionally substituted C 2 -10 alkenyl. In some embodiments, R lc is substituted C 2 -15 alkenyl. In some embodiments, R lc is substituted C 2 -10 alkenyl. In some embodiments, R lc is unsubstituted C 2 -15 alkenyl. In some embodiments, R lc is unsubstituted C 2-10 alkenyl.
  • R lc is optionally substituted carbocyclyl. In some embodiments, R lc is optionally substituted C 3 _ 6 carbocyclyl. In some embodiments, R lc is optionally substituted heterocyclyl. In some embodiments, R lc is optionally substituted 3- to 6- membered heterocyclyl. In some embodiments, R lc is optionally substituted 6-membered heterocyclyl with one heteroatom selected from the group consisting of N, O, and S. In some embodiments, R lc is optionally substituted 6- membered heterocyclyl with two heteroatoms each independently selected from the group consisting of N, O, and S.
  • R lc is optionally substituted 6- membered heterocyclyl with three heteroatoms each independently selected from the group consisting of N, O, and S. In some embodiments, R lc is optionally substituted 5- membered heterocyclyl with one heteroatom selected from the group consisting of N, O, and S. In some embodiments, R lc is optionally substituted 5-membered heterocyclyl with two heteroatoms each independently selected from the group consisting of N, O, and S. In some embodiments, R lc is optionally substituted aryl. In some embodiments, R lc is optionally substituted phenyl. In some embodiments, R lc is phenyl. In some embodiments, R lc is optionally substituted heteroaryl. In some embodiments, R lc is optionally
  • R lc is optionally substituted 6-membered heteroaryl with one heteroatom selected from the group consisting of N, O, and S.
  • R lc is optionally substituted 6- membered heteroaryl with two heteroatoms each independently selected from the group consisting of N, O, and S.
  • R lc is optionally substituted 5- membered heteroaryl with one heteroatom selected from the group consisting of N, O, and S.
  • R lc is optionally substituted 5-membered heteroaryl with two heteroatoms each independently selected from the group consisting of N, O, and S.
  • heterocyclyl optionally substituted aryl, optionally substituted heteroaryl, or OR°;
  • R° is independently hydrogen, optionally substituted alkyl, or an oxygen protecting group.
  • R c is OR°; and R° is optionally substituted C 1-6 alkyl.
  • R lc is of one of the following formulae:
  • ml is 0 or an integer of 1 to 15, inclusive. In certain embodiments, ml is 0. In certain embodiments, ml is an integer of 1 to 15, inclusive. In certain embodiments, ml is an integer of 5 to 15, inclusive. In certain embodiments, ml is an integer of 5 to 10, inclusive. In certain embodiments, ml is an integer of 10 to 15, inclusive. In certain embodiments, ml is an integer of 1 to 10, inclusive. In certain embodiments, ml is an integer of 1 to 5, inclusive.
  • m2 is 0 or an integer of 1 to 15, inclusive. In certain embodiments, m2 is 0. In certain embodiments, m2 is an integer of 1 to 15, inclusive. In certain embodiments, m2 is an integer of 5 to 15, inclusive. In certain embodiments, m2 is an integer of 5 to 10, inclusive. In certain embodiments, m2 is an integer of 10 to 15, inclusive. In certain embodiments, m2 is an integer of 1 to 10, inclusive. In certain embodiments, m2 is an integer of 1 to 5, inclusive.
  • m2 is of one of the following formulae:
  • CoA refers to coenzyme A (CoA, Co ASH, or HSCoA), a coenzyme, notable for its role in the synthesis and oxidation of fatty acids, and the oxidation of pyruvate in the citric acid cycle.
  • the structure of free CoA is as follows:
  • CoA When CoA is attached to an acyl group, the point of attachment on CoA is at the thiol group.
  • the acyl-donor of Formula (S-i) is of Formula (S-i-a)
  • NAC refers to acetylcysteamine (also known as N- acetylcysteamine).
  • NAC acetylcysteamine
  • the point of attachment on NAC is at the thiol group.
  • the acyl-donor of Formula (S-ii) is of the Formula (S-ii-a)
  • X is of Formula (i):
  • Y is hydrogen or of Formula (ii):
  • each instance of R is independently optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, or -OR°;
  • each instance of R° is independently hydrogen, optionally substituted alkyl, or an oxygen protecting group
  • each of R p and R q is independently hydrogen, optionally substituted Ci_6 alkyl, an optionally substituted carbohydrate, or an oxygen protecting group;
  • n is 0 or an integer of 1 to 15, inclusive
  • n is 0 or an integer of 1 to 15, inclusive.
  • the provided method generates a teicoplanin analog of Formula (I- a):
  • R 1; R 2 , m, and Z are as defined herein.
  • the provided method generates a teicoplanin analog of Formula (I-b):
  • Rl, R2, m, and Z are as defined herein.
  • the provided method generates a teicoplanin analog of Formula I) wherein Y is hydrogen and X is one of the following formulae:
  • the provided method generates a teicoplanin analog of any one of compounds listed in Table Al.
  • alkyl refers to a straight-chained or branched alkyl group containing 1 to 6 carbon atoms. Examples of alkyl groups include methyl, ethyl, n- propyl, isopropyl, ie/t-butyl, and n-pentyl.
  • alkenyl or alkynyl refers to a straight-chained or branched alkenyl or alkynyl group containing 2 to 6 carbon atoms.
  • alkyloxyl refers to an -O-alkyl radical.
  • aryl refers to a hydrocarbon ring system (mono-cyclic or bi-cyclic) having at least one aromatic ring.
  • aryl moieties include, but are not limited to, phenyl, naphthyl, and pyrenyl.
  • heteroaryl refers to a hydrocarbon ring system (mono-cyclic or bi- cyclic) having at least one aromatic ring which contains at least one heteroatom such as O, N, or S as part of the ring system and the reminder being carbon.
  • heteroaryl moieties include, but are not limited to, furyl, pyrrolyl, thienyl, oxazolyl, imidazolyl, thiazolyl, pyridinyl, pyrimidinyl, quinazolinyl, and indolyl.
  • cyclyl and heterocyclyl refer to a partially or fully saturated mono- cyclic or bi-cyclic ring system having from 4 to 14 ring atoms.
  • a heterocyclyl ring contains one or more heteroatoms (e.g., O, N, or S) as part of the ring system and the remainder being carbon.
  • exemplary cyclyl and heterocyclyl rings are cyclohexane, piperidine, piperazine, morpholine, thiomorpholine, and 1,4-oxazepane.
  • alkyl, alkenyl, alkynyl, aryl, heteroaryl, cyclyl, and heterocyclyl mentioned herein include both substituted and unsubstituted moieties.
  • substituted refers to one or more substituents (which may be the same or different), each replacing a hydrogen atom.
  • substituents include, but are not limited to, halogen, cyano, nitro, hydroxyl, amino, mercapto, alkyl, alkenyl, alkynyl, aryl, heteroaryl, cyclyl, heterocyclyl, alkyloxy, aryloxy, alksulfanyl, arylsulfanyl, alkylamino, arylamino, dialkylamino, diarylamino, alkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, alkylcarboxyl, arylcarboxyl, heteroarylcarboxyl, alkyloxycarbonyl, aryloxycarbonyl, heteroaryloxycarbonyl, alkylcarbamido, arylcarbamido, heterocarbamido, alkylcarbamyl, arylcarbamyl, heterocarbamyl, wherein each of alkyl (including alk), alkenyl, aryl, heteroaryl,
  • Another aspect of the present invention relates to a pharmaceutical composition that contains a pharmaceutically acceptable carrier and an effective amount of at least one of the provided compounds described above.
  • the present invention provides methods for inhibiting bacterial growth and/or microbial infection s comprising administering to a subject a
  • the present invention provides methods for treating a bacterial infection comprising administering to a subject a therapeutically effective amount of a compound of Formula (I), or a pharmaceutical acceptable salt thereof.
  • the bacterium is a gram-positive bacterium. In certain embodiments, the bacterium is at least one selected from the group consisting of
  • MRSE methicillin-resistant Staphylococcus Epidermidis
  • penicillin-resistant Streptococcus pneumonia quinolone-resistant
  • Staphylococcus Aureus QRSA
  • vancomycin-resistant Staphylococcus Aureus VRSA
  • vancomycin-resistant Enterococci VRE
  • multi-drug resistant Mycobacterium tuberculosis
  • the salts can be formed between a positively charged substituent (e.g., amino) on a compound and an anion.
  • Suitable anions include, but are not limited to, chloride, bromide, iodide, sulfate, nitrate, phosphate, citrate, methanesulfonate, trifluoroacetate, and acetate.
  • a negatively charged substituent (e.g., carboxylate) on a compound can form a salt with a cation.
  • Suitable cations include, but are not limited to, sodium ion, potassium ion, magnesium ion, calcium ion, and an ammonium cation such as
  • prodrugs include esters and other
  • compositions containing one or more of the provided compounds described above for use in treating diseases or disorders described above are also within the scope of this invention.
  • Figure 1 shows chemical structures of glycopeptides and coenzyme A derivatives.
  • Compound 1 teicoplanin A2-2 (brached chain) and A2-3 (straight chain) (referred to here as teicoplanin, Tei), compound 2: A40926, compound 3: Tei pseudoaglycone, compound 4: decanoly-CoA, compound 5: coenzyme A (CoA), compound 6: vancomycin (Van), compound 7: octyl-derivatiezed Van (Cg-Van), compound 8: decanoyl-N-acetyl cysteamine (decanoyl-NAC), compound 9: octyl- substituted Tei, compound 10: octyl- CoA, compound 11: diacyl-teicoplanin (C8,Cio-Tei), compound 12: CoA-disulfide, compound 17: ⁇ -octyl glucoside ( ⁇ -OG), octyl-
  • Figure 2 shows structures of Orf 11* and Dbv8.
  • the apo structure of Orf 11* is shown in the left panel.
  • this domain consists of eight cc-helices (ccl-cc8).
  • this domain is composed of a five-stranded ⁇ -sheet ( ⁇ - ⁇ 5) and five cc-helices (cc9-ccl3) (right panel),
  • Orf 11* and Dbv8 were superimposed with the rmsd of 1.093 A for 310 Ca.
  • (d) View of the lipid tunnel in
  • Figure 3 shows the active site views of Orfl l* and its enzymatic mechanisms, (a) The structural views for three reaction states - pre-acylation (left), tetrahedron
  • Figure 4 shows liquid chromatography (LC) traces and mass spectra, (a) LC traces: (i) CoA 5, (ii) octyl-CoA 10, (iii) decanoyl-CoA 4, (iv) Tei pseudoaglycone 3, (v) Tei 1 (major: A2-2 and A2-3, minor: A2-1, A2-4, A2-5 and RSI to RS4), (vi) Van 6, (vii) formation of CoA-disulfide 12 in an enzymatic reaction with addition of decanoyl-CoA 4, (viii) formation of Tei 1 and diacyl-teicoplanin (CicCio-Tei) 19 in an enzymation reaction with addition of decanoyl-CoA 4 and Tei pseudoaglycone 3, (ix) formation of Tei 1 (A2-3) in an enzymation reaction with addition of decanoyl-NAC 8 and Tei pseudoaglycone 3, (x) formation
  • Figure 5 shows structures of oxidation products in the active site of Orf 11* and their proposed mechanisms, (a) The structure of CoA-disulfide 12. (b) The structure of sulfurperoxide-CoA 13. (c) The structure of sulfenyl-CoA 14. (d) The structure of decanoylperoxide 15. (e) The proposed mechanism for CoA oxidation, (f) The structure of decanoylperoxide-CoA 16. (g) The proposed mechanism for the formation of decanoylperoxide-CoA 16 and decanoylperoxide 15. (h) The structures of (lR)-octanol peroxide-CoA 18 and ⁇ / ⁇ -D-glucose.
  • Figure 6 shows analytical ultracentrifugation analysis of Orfl l*
  • Orfl l */decanoyl-CoA and Orfl l */decanoyl-CoA/Tei pseudoaglycone were analyzed using SedFit (http://www.analyticalultracentrifugation.com/default.htm).
  • the calculated c(M) and c(S) distributions are shown in panels (a) (c) (e) and panels (b) (d) (f), respectively.
  • the insert grayscale bars indicate the residuals bitmap in each fit.
  • Figure 7 shows structural alignment of Orfll* and its N-terminal domain. This structural alignment was performed using the DALI server.
  • the overall structure of Orfll* belongs to the protein family of acetyltransferases.
  • the N-terminal all-helix domain belongs to the protein family of AAA atpases.
  • Z score the statistical significance of the similarity between protein-of-interest and other neighborhood proteins.
  • RMSD the root-mean-square deviation of C-alpha atoms in the least-squares superimposition of the structurally equivalent C-alpha atoms.
  • Lali the number of structurally equivalent residues.
  • Nres the total number of amino acids in the hit protein.
  • % id the percentage of identical amino acids over structurally equivalent residues.
  • Figure 8 shows ligplot diagram of the interaction between decanoyl-CoA and Orf 11*. This plot was generated using the Ligplot software.
  • Figure 9 shows isothermal titration calorimetry (ITC) analysis of Orfl l*. ITC thermograms of Orfll* versus CoA, acetyl-CoA, butyryl-CoA, hexanoyl-CoA, octanoyl- CoA, decanoyl-CoA, lauroyl-CoA, myristoyl-CoA, palmitoyl-CoA, stearoyl-CoA or Tei- pseudoaglycone.
  • ITC isothermal titration calorimetry
  • Each exothermic heat pulse corresponds to an injection of 2 ⁇ of ligands (1 mM ⁇ 5 mM) into a protein solution (0.1 mM); integrated heat areas constitute a differential binding curve that was fitted with a standard single- site binding model (Origin 7.0, MicroCal iTC 20 o).
  • Figure 10 shows the binding site of Tei pseudoaglycone in Orfll*.
  • the 2F 0 -F C electron density map of Tei pseudaoglycone is contoured at 1 ⁇ .
  • the Ligplot diagram shows the binding site of the r4 glucosamine in the complex.
  • Figure 11 shows the structures and mass spectra of (a) ClO-vancomycin and (b) C8-vancomycin.
  • Figure 12 shows the structure and mass spectrum of decanoyl-NAC.
  • Figure 13 shows the structures and mass spectra of (a) 2N-decanoyl, 60-octyl-Tei and (b) octyl-Tei.
  • Figures 14a and 14b show schematic topologies of Orfll* and Dbv8. The topology diagrams were generated using TopDraw.
  • Orfll */Dbv8 is composed of two domains, an N- terminal all-helix domain (residues 1-170) and a C-terminal GNAT domain (residues 171- 322/residues 171-318 for Orfll*/Dbv8).
  • Figure 15 shows NMR spectra include 1H, 13C, COSY, HSQC, HMBC, and NOESY of Compound 7.
  • Figure 16 shows NMR information for compound 9.
  • NMR spectra include 1H, 13 C, COSY, HSQC, HMBC, and NOESY
  • Figure 17 shows NMR information for compound 11.
  • NMR spectra include 1H,
  • Figure 18 shows the LC traces (a) and mass spectra (b-q) for major acylated Tei derivatives generated in the enzymatic reactions catalysed by Orfll*.
  • Figure 19 shows Table 1: data collection, phasing and refinement statistics for structures of Dbv8, Orfll* and mutants thereof. Highest resolution shell is shown in parenthesis.
  • Figure 20 shows Table 2: structures of acyl-CoAs and their availability in enzymatic reactions. The enzymatic activities were determined by LC/MS. "+” represents the given acyl-CoA can be utilized by Orfll* to generate corresponding acyl Tei derivatives. Malonyl-, isobutyryl-, methylmalonyl- and benzoyl-CoA cannot be utilized by Orfll* due to steric hindrance. Major LC traces and mass spectra for positive reactions are shown in Figure 18.
  • Figure 21 shows Table 3: relative enzymatic activities of mutants and proposed functions for the selected residues, a.
  • the activities of mutants were determined by HPLC.
  • the reaction rates were calculated using the linear regression equation on the basis of averaged peak areas in triplicate.
  • the relative activities were determined by dividing individual reaction rates with that of WT, where the relative activity of WT is 100%.
  • Figure 23 shows Table 5: NMR assignments for compound 9.
  • Figure 24 shows Table 6: NMR assignments for compound 11.
  • Figure 25 shows exemplified reactions catalyzed by Orfll to provide Tei analogs.
  • Reaction 1 conditions the reaction mixture (total volume 500 ⁇ ), containing Orfllb (final cone. 0.01 mM), teicoplanin (final cone. 2 mM) and acyl-CoA (final cone. 1 mM) or acyl-NAC (final cone. 2.5 mM) + CoA (final cone. 1 mM) in a Tris buffer solution (0.1 M Tris-base pH 9.0, 0.1 M NaCl, 25% DMSO), was incubated for 4 h at 30°C.
  • Tris buffer solution 0.1 M Tris-base pH 9.0, 0.1 M NaCl, 25% DMSO
  • Reaction 2 conditions The reaction mixture (total volume 500 ⁇ ), containing Orfllb (final cone. 0.01 mM), teicoplanin (final cone. 2 mM) and acyl-CoA (final cone. 1 mM) or acyl-NAC (final cone. 2.5 mM) + CoA (final cone. 1 mM) in a Tris buffer solution (0.1 M Tris-base pH 6.5-7.5, 0.1 M NaCl, 25% DMSO), was incubated for 4 h at 30°C.
  • Figure 26 is a photo showing the MIC values determined by the broth
  • NCCLS Laboratory Standards
  • the present invention provides pharmaceutical compositions comprising a compound described herein, e.g., a compound of Formulae (I), or a pharmaceutically acceptable salt thereof.
  • the present invention also provides pharmaceutical compositions for use in treating a bacterial infection comprising a compound described herein, e.g., a compound of Formulae (I), and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled derivatives, and prodrugs thereof, and optionally a pharmaceutically acceptable excipient.
  • a provided composition comprises two or more compounds described herein.
  • a compound described herein, or a pharmaceutically acceptable salt thereof is provided in an effective amount in the pharmaceutical composition.
  • the effective amount is a therapeutically effective amount.
  • the effective amount is an amount effective for inhibiting bacterial growth .
  • the effective amount is an amount effective for treating or preventing microbial infection.
  • the bacterium is a gram-positive bacterium. In certain embodiments, the bacterium is at least one selected from the group consisting of
  • the bacterium is at least one selected from the group consisting of methicillin-resistant Staphylococcus Aureus (MRSA), methicillin- resistant Staphylococcus Epidermidis (MRSE), penicillin-resistant Streptococcus pneumonia, quinolone-resistant Staphylococcus Aureus (QRSA), vancomycin-resistant Staphylococcus Aureus (VRSA), vancomycin-resistant Enterococci (VRE), or multi-drug resistant Mycobacterium tuberculosis.
  • MRSA methicillin-resistant Staphylococcus Aureus
  • MRSE methicillin- resistant Staphylococcus Epidermidis
  • QRSA quinolone-resistant Staphylococcus Aureus
  • VRSA vancomycin-resistant Staphylococcus Aureus
  • VRE vancomycin-resistant Enterococci
  • the present invention provides compounds and pharmaceutical compositions useful for inhibiting bacterial growth.
  • the present invention provides methods for inhibiting bacterial growth comprising administering an effective amount of a compound described herein (e.g., a compound of Formula (I)), a pharmaceutically acceptable salt thereof), a solvate, a hydrate, a polymorph, a co-crystal, a tautomer, a stereoisomer, an isotopically labeled derivative, or a prodrug thereof, as described herein, and optionally a pharmaceutically acceptable excipient to a subject in need of treatment.
  • a compound described herein e.g., a compound of Formula (I)
  • a pharmaceutically acceptable salt thereof e.g., a compound of Formula (I)
  • a solvate e.g., a compound of Formula (I)
  • a hydrate e.g., a compound of Formula (I)
  • a pharmaceutically acceptable salt thereof e.g., a solvate
  • the present invention provides methods for treating or preventing microbial infection comprising administering an effective amount of a compound described herein (e.g., a compound of Formula (I)), or a pharmaceutically acceptable salt thereof), to a subject in need of treatment.
  • the effective amount is a therapeutically effective amount.
  • the effective amount is a prophylactically effective amount.
  • the subject is suffering from at least one bacterial infection.
  • a method of treating or preventing microbial infection caused by pathogen that are resistant to other treatments for example, multidrug tolerant or resistant and/or that neither grow nor die in the presence of or as a result of other treatments.
  • Such a method can be conducted in vivo (i.e. , by administration to a subject) or in vitro (e.g. , upon contact with bacteria in a cell culture).
  • a method of treating and/or preventing microbial infection comprising administering an effective amount of a compound of the present invention, e.g. , a compound of Formula (I) or a pharmaceutically acceptable salt thereof, to a subject with a microbial infection .
  • provided is a method of treating microbial infection comprising contacting an effective amount of the compound of the present invention with a microorganism.
  • an in vitro method of treating microbial infection comprising contacting an effective amount of the compound of the present invention with a microorganism in a cell culture.
  • an in vivo method of treating microbial infection comprising administering an effective amount of the compound of the present invention to a subject with a microbial infection.
  • the microorganism is a bacterium.
  • Exemplary bacterial infections include, but are not limited to, infections with a gram positive bacteria (e.g., of the phylum Actinobacteria, phylum Firmicutes, or phylum Tenericutes); gram negative bacteria (e.g., of the phylum Aquificae, phylum Deinococcus- Thermus, phylum Fibwbacteres/Chlorobi/Bacteroidetes (FCB), phylum Fusobacteria, phylum Gemmatimonadest, phylum Ntrospirae, phylum
  • Planctomycetes/Verrucomicrobia/Chlamydiae PVC
  • phylum Proteobacteria phylum Spirochaetes
  • phylum Synergistetes e.g., of the phylum
  • Acidobacteria phylum Chlroflexi, phylum Chrystiogenetes, phylum Cyanobacteria, phylum Deferrubacteres, phylum Dictyoglomi, phylum Thermodesulfobacteria, or phylum Thermotogae).
  • the bacterial infection is an infection with a gram positive bacteria.
  • the gram positive bacteria is a bacteria of the phylum Firmicutes.
  • the bacteria is a member of the phylum Firmicutes and the genus Enterococcus, i.e., the bacterial infection is an Enterococcus infection.
  • Exemplary Enterococci bacteria include, but are not limited to, E. avium, E. durans, E. faecalis, E. faecium, E. gallinarum, E. solitarius, E. casseliflavus, and E. raffinosus.
  • the Enterococcus infection is an E. faecalis infection.
  • the Enterococcus infection is an E. faecium infection.
  • the bacteria is a member of the phylum Firmicutes and the genus Staphylococcus, i.e., the bacterial infection is a Staphylococcus infection.
  • Exemplary Staphylococci bacteria include, but are not limited to, S. arlettae, S. aureus, S. auricularis, S. capitis, S. caprae, S. carnous, S. chromogenes, S. cohii, S. condimenti, S. croceolyticus, S. delphini, S. devriesei, S. epidermis, S. equorum, S. felis, S. fluroettii, S. gallinarum, S. haemolyticus, S. hominis, S. hyicus, S. intermedius, S. kloosii, S. leei, S. lenus, S. lugdunesis, S. lutrae, S. lyticans, S. massiliensis, S. microti, S. muscae, S.
  • the Staphylococcus infection is an S. aureus infection.
  • the Staphylococcus infection is an S. epidermis infection.
  • the bacterial infection is resistant to other antibiotic therapy.
  • the bacterial infection is vancomycin resistant (VR).
  • the bacterial infection is a vancomycin-resistant E. faecalis infection. In certain embodiments, the bacterial infection is a vancomycin- resistant E. faecium infection. In certain embodiments, the bacterial infection is a methicillin-resistant (MR). In certain embodiments, the bacterial infection is a methicillin-resistant S. aureus (MRSA) infection.
  • MR methicillin-resistant
  • MRSA methicillin-resistant S. aureus
  • the present invention provides a method for producing an antibacterial effect in a subject comprising administering an effective amount of a compound described herein or a pharmaceutically-acceptable salt thereof.
  • the invention provides a method for inhibition of PGT in subject comprising administering to the subject an effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof as defined hereinbefore.
  • a method of treating a bacterial infection and/or virulence including the treatment of bacteria or infection caused by bacteria that are resistant to other treatments, are multi-drug tolerant or resistant and/or that neither grow nor die in the presence of or as a result of other treatments.
  • Such a method can be conducted in vivo ⁇ i.e. , by administration to a subject) or in vitro ⁇ e.g. , upon contact with bacteria in a cell culture).
  • a method of treating bacterial virulence comprising administering an effective amount of a compound of the present invention e.g. , a compound of Formula (I), or a pharmaceutically acceptable salt thereof, to a subject with a bacterial infection.
  • the compound blocks virulence factor production.
  • the compounds of the present invention inhibit the growth of or kill rapidly dividing cells such as stimulated inflammatory cells.
  • the present invention also contemplates the treatment of a disease, disorder, or condition associated with abnormal cellular proliferation, such as cancer, autoimmune diseases, inflammatory diseases, and diabetic retinopathy.
  • a method of treating cancer comprising administering an effective amount of the compound of the present invention or pharmaceutically acceptable salt thereof to a subject.
  • provided is a method of treating an autoimmune disease comprising administering an effective amount of the compound of the present invention or pharmaceutically acceptable salt thereof to a subject.
  • a method of treating an inflammatory disease comprising administering the compound of the present invention or pharmaceutically acceptable salt thereof to a subject.
  • compositions of the present invention are typically formulated in dosage unit form for ease of administration and uniformity of dosage. It will be understood, however, that the total daily usage of the compositions of the present invention will be decided by the attending physician within the scope of sound medical judgment.
  • the specific therapeutically effective dose level for any particular subject or organism will depend upon a variety of factors including the disease, disorder, or condition being treated and the severity of the disorder; the activity of the specific active ingredient employed; the specific composition employed; the age, body weight, general health, sex and diet of the subject; the time of administration, route of administration, and rate of excretion of the specific active ingredient employed; the duration of the treatment; drugs used in combination or coincidental with the specific active ingredient employed; and like factors well known in the medical arts.
  • the compounds and compositions provided herein can be administered by any route, including enteral (e.g. , oral), parenteral, intravenous, intramuscular, intra-arterial, intramedullary, intrathecal, subcutaneous, intraventricular, transdermal, interdermal, rectal, intravaginal, intraperitoneal, topical (as by powders, ointments, creams, and/or drops), mucosal, nasal, bucal, sublingual; by intratracheal instillation, bronchial instillation, and/or inhalation; and/or as an oral spray, nasal spray, and/or aerosol.
  • enteral e.g. , oral
  • parenteral intravenous
  • intramuscular intra-arterial
  • intramedullary intrathecal
  • subcutaneous intraventricular
  • transdermal transdermal
  • interdermal interdermal
  • rectal intravaginal
  • topical as by powders, ointments, creams, and/or drops
  • systemic intravenous injection regional administration via blood and/or lymph supply, and/or direct administration to an affected site.
  • direct administration to an affected site.
  • the most appropriate route of administration will depend upon a variety of factors including the nature of the agent (e.g. , its stability in the environment of the gastrointestinal tract), the condition of the subject (e.g. , whether the subject is able to tolerate oral administration), etc.
  • a sterile injectable composition e.g., a sterile injectable aqueous or oleaginous suspension
  • a sterile injectable preparation can be formulated according to techniques known in the art using suitable dispersing or wetting agents (such as Tween 80) and suspending agents.
  • the sterile injectable preparation can also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol.
  • suitable vehicles and solvents that can be employed are mannitol, water, Ringer's solution and isotonic sodium chloride solution.
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium (e.g., synthetic mono- or diglycerides).
  • Fatty acids such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceutically- acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions.
  • These oil solutions or suspensions can also contain a long-chain alcohol diluent or dispersant, or carboxymethyl cellulose or similar dispersing agents.
  • Other commonly used surfactants such as Tweens or Spans or other similar emulsifying agents or bioavailability enhancers which are commonly used in the manufacture of pharmaceutically acceptable solid, liquid, or other dosage forms can also be used for the purposes of formulation.
  • a composition for oral administration can be any orally acceptable dosage form including, but not limited to, capsules, tablets, emulsions and aqueous suspensions, dispersions and solutions.
  • carriers which are commonly used include lactose and corn starch.
  • Lubricating agents, such as magnesium stearate, are also typically added.
  • useful diluents include lactose and dried corn starch.
  • a nasal aerosol or inhalation composition can be prepared according to techniques well-known in the art of pharmaceutical formulation and can be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and/or other solubilizing or dispersing agents known in the art.
  • An indole compound-containing composition can also be administered in the form of suppositories for rectal administration.
  • the carrier in the pharmaceutical composition must be "acceptable” in the sense of being compatible with the active ingredient of the formulation (and preferably, capable of stabilizing it) and not deleterious to the subject to be treated.
  • solubilizing agents such as cyclodextrins, which form specific, more soluble complexes with the indole compounds, or one or more solubilizing agents, can be utilized as pharmaceutical excipients for delivery of the compounds described herein.
  • examples of other carriers include colloidal silicon dioxide, magnesium stearate, cellulose, sodium lauryl sulfate, and D&C Yellow # 10. See, e.g., Remington's Pharmaceutical Sciences, Edition 16, Mack Publishing Co., Easton, Pa (1980); and Goodman and Gilman's "The
  • the desired dosage can be delivered three times a day, two times a day, once a day, every other day, every third day, every week, every two weeks, every three weeks, or every four weeks.
  • the desired dosage can be delivered using multiple administrations (e.g. , two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, or more
  • an effective amount of a compound for administration one or more times a day to a 70 kg adult human may comprise about 0.0001 mg to about 3000 mg, about 0.0001 mg to about 2000 mg, about 0.0001 mg to about 1000 mg, about 0.001 mg to about 1000 mg, about 0.01 mg to about 1000 mg, about 0.1 mg to about 1000 mg, about 1 mg to about 1000 mg, about 1 mg to about 100 mg, about 10 mg to about 1000 mg, or about 100 mg to about 1000 mg, of a compound per unit dosage form.
  • the compounds of the invention may be administered orally or parenterally at dosage levels sufficient to deliver from about 0.001 mg/kg to about 100 mg/kg, from about 0.01 mg/kg to about 50 mg/kg, preferably from about 0.1 mg/kg to about 40 mg/kg, preferably from about 0.5 mg/kg to about 30 mg/kg, from about 0.01 mg/kg to about 10 mg/kg, from about 0.1 mg/kg to about 10 mg/kg, and more preferably from about 1 mg/kg to about 25 mg/kg, of subject body weight per day, one or more times a day, to obtain the desired therapeutic effect.
  • dose ranges as described herein provide guidance for the administration of provided pharmaceutical compositions to an adult.
  • the amount to be administered to, for example, a child or an adolescent can be determined by a medical practitioner or person skilled in the art and can be lower or the same as that administered to an adult.
  • a compound or composition, as described herein, can be administered in combination with one or more additional therapeutically active agents.
  • the compounds or compositions can be administered in combination with additional therapeutically active agents that improve their bioavailability, reduce and/or modify their metabolism, inhibit their excretion, and/or modify their distribution within the body.
  • the therapy employed may achieve a desired effect for the same disorder, and/or it may achieve different effects.
  • the compound or composition can be administered concurrently with, prior to, or subsequent to, one or more additional therapeutically active agents. In general, each agent will be administered at a dose and/or on a time schedule determined for that agent.
  • the additional therapeutically active agent utilized in this combination can be administered together in a single composition or administered separately in different compositions.
  • the particular combination to employ in a regimen will take into account compatibility of the inventive compound with the additional therapeutically active agent and/or the desired therapeutic effect to be achieved. In general, it is expected that additional therapeutically active agents utilized in combination be utilized at levels that do not exceed the levels at which they are utilized individually.
  • the levels utilized in combination will be lower than those utilized individually.
  • Exemplary additional therapeutically active agents include, but are not limited to, antibiotics, anti-viral agents, anesthetics, anti-coagulants, inhibitors of an enzyme, steroidal agents, steroidal or non-steroidal anti-inflammatory agents, antihistamine, immunosuppressant agents, antigens, vaccines, antibodies, decongestant, sedatives, opioids, pain-relieving agents, analgesics, anti-pyretics, hormones, and prostaglandins, etc.
  • Therapeutically active agents include small organic molecules such as drug compounds (e.g.
  • CFR Code of Federal Regulations
  • the additional therapeutically agent is an antibiotic.
  • antibiotics include, but are not limited to, penicillins (e.g. , penicillin, amoxicillin), cephalosporins (e.g. , cephalexin), macrolides (e.g. , erythromycin, clarithormycin, azithromycin, troleandomycin), fluoroquinolones (e.g. , ciprofloxacin, levofloxacin, ofloxacin), sulfonamides (e.g. , co-trimoxazole, trimethoprim), tetracyclines (e.g.
  • penicillins e.g. , penicillin, amoxicillin
  • cephalosporins e.g. , cephalexin
  • macrolides e.g. , erythromycin, clarithormycin, azithromycin, troleandomycin
  • fluoroquinolones e.g. , ciprofloxacin, levofloxacin, oflox
  • tetracycline chlortetracycline, oxytetracycline, demeclocycline, methacycline, sancycline, doxycline, aureomycin, terramycin, minocycline, 6-deoxytetracycline, lymecycline, meclocycline, methacycline, rolitetracycline, and glycylcycline antibiotics (e.g. , tigecycline)), aminoglycosides (e.g. , gentamicin, tobramycin, paromomycin), aminocyclitol (e.g., spectinomycin), chloramphenicol, sparsomycin,
  • aminoglycosides e.g. , gentamicin, tobramycin, paromomycin
  • aminocyclitol e.g., spectinomycin
  • chloramphenicol sparsomycin
  • the antibiotic is a ribosome-targeting antibiotic.
  • Antibiotics target ribosomes at distinct locations within functionally relevant sites. They exert their inhibitory action by diverse modes, including competing with substrate binding, interfering with ribosomal dynamics, minimizing ribosomal mobility, facilitating miscoding, hampering the progression of the mRNA chain, and blocking the nascent protein exit tunnel.
  • antibiotics that reveal novel ribosomal properties or enforced otherwise observed findings include the following: decoding (paromomycin); mRNA progression (spectinomycin); A-site binding to the small (tetracycline antibiotic) and the large (chloramphenicol) subunits; PTC mobility (sparsomycin); tRNA rotatory motion (quinupristin/dalfoprisin), and tunnel gating (troleandomycin); see Yonath, Annu. Rev. Biochem. (2005) 74:649-679.
  • one aspect of the present disclosure provides methods for preparing novel teicoplanin compound as described herein, including di-acyl teicoplanin analogs (2-acylamide, 6-acyl ester teicoplanin analogs) and teicoplanin compounds having a single uniform acyl group, using a long lipid chain acyltransferase ( Figure 25).
  • a long lipid chain acyltransferase is an enzyme that catalyzes the acylation reaction by transferring a long lipid side chain from an acyl donor to an acyl acceptor.
  • the long lipid chain acyltransferase for use in the preparation methods described herein can be a naturally- occurring enzyme, or a functional variant thereof.
  • acyltransferases for use in the preparation methods described herein include Orfllb and Dbv8.
  • the long lipid chain acyltransferases for use in the preparation methods described herein is Orfllb.
  • the long lipid chain acyltransferases for use in the preparation methods described herein is Dbv8.
  • Figure 7 shows the structural alignment of Orfllb with its homologs.
  • acyltransferase can be mixed with an acyl-acceptor and an acyl-donor under conditions allowing for occurrence of the enzymatic reaction catalyzed by the long-chain
  • the acyl-acceptor is of Formula (I-c) as described herein and the acyl-donor can be Formula (S-ii) or (S-iii) described herein.
  • the acyl-donor is of Formula (S-ii).
  • the acyl-donor is of Formula (S-iii).
  • the acyl-donor is of Formula (S- ii) and the reaction mixture further comprises free CoA.
  • the acyl- donor is of Formula (S-iii) and the reaction mixture further comprises free CoA.
  • the preparation method is preferred to be carried out under a pH value of 8-10 (e.g., pH of 9).
  • a pH value of 6-8 e.g., 6.5-7.5.
  • the acyltransferase can be of catalytic amount in the provided method.
  • the molar ratio of the acyltransferase to the acyl acceptor is from about 1000: 1 to about 1: 1. In certain embodiments, the molar ratio of the acyltransferase to the acyl acceptor is about 800: 1 to about to about 10: 1. In certain embodiments, the molar ratio of the acyltransferase to the acyl acceptor is about 600: 1 to about 1: 1. In certain embodiments, the molar ratio of the acyltransferase to the acyl acceptor is about 400 to 1 to about 50: 1.
  • the molar ratio of the acyltransferase to the acyl acceptor is about 300: 1 to about 80: 1. In certain embodiments, the molar ratio of the acyltransferase to the acyl acceptor is about 200: 1 to about 100: 1. In certain embodiments, the molar ratio of the acyltransferase to the acyl acceptor is about 200: 1.
  • the molar ratio of the acyl donor to the acyl acceptor is about 1: 100 to about 100: 1. In certain embodiments, the molar ratio of the acyl donor to the acyl acceptor is about 1: 50 to about 50: 1. In certain embodiments, the molar ratio of the acyl donor to the acyl acceptor is about 1: 20 to about 20: 1. In certain embodiments, the molar ratio of the acyl donor to the acyl acceptor is about 1: 10 to about 10: 1. In certain embodiments, the molar ratio of the acyl donor to the acyl acceptor is about 1 : 5 to about 5: 1.
  • the molar ratio of the acyl donor to the acyl acceptor is about 1: 3 to about 3: 1. In certain embodiments, the molar ratio of the acyl donor to the acyl acceptor is about 1: 2.5. In certain embodiments, the molar ratio of the acyl donor to the acyl acceptor is about 1: 2.
  • the suitable condition for the provided preparation method also includes presence of a buffer solution. It is understood that the choice of buffer depends on the target pH for the acyl-transferation to occur.
  • the buffer solution is a Tris buffer solution.
  • the Tris buffer solution is at a pH of about 6.0 to about 8.0 to prepare mono-acylation teicoplanin compounds.
  • the Tris buffer solution is at a pH of about 6.5 to about 7.5 to prepare mono-acylation teicoplanin compounds.
  • the Tris buffer solution is at a pH of about 8.0 to about 10.0 to prepare diacylation teicoplanin compounds.
  • the Tris buffer solution is at a pH of about 9.0 to prepare diacylation teicoplanin compounds.
  • the suitable condition may further includes presence of free CoA which act to facilitate the acyltransferation.
  • the amount of CoA is about 10 to 0.1 equivalent to the acyl donor. In certain embodiments, the amount of CoA is about 5 to 0.5 equivalent to the acyl donor. In certain embodiments, the amount of CoA is about 2 to 0.5 equivalent to the acyl donor. In certain embodiments, the amount of CoA is about 1 equivalent to the acyl donor.
  • Example 1 Long chain acyltransferase and uses thereof in preparing teicoplanin analogs
  • Cells were harvested by centrifugation at 6000 rpm for 20 min at 4°C, resuspended in 30 mL binding buffer (50 mM Tris at pH 8.0, 500 mM NaCl, 10 mM imidazole, 10% glycerol) and disrupted by microfluidizer. The cell lysate was centrifuged at 18000 rpm for 30 minutes to remove cell debris. The supernatant was applied to a Ni 2+ -NTA agarose resin column (2 mL,
  • the buffer was exchanged using Millipore centrifugal filters and HEPES buffer (50 mM, pH 8.0). Protein purity was determined by SDS-PAGE and Western blotting, and electrospray mass spectrometry (ESI-MS). Protein concentrations were estimated using the Bradford assay.
  • Site-directed mutagenesis Site-directed mutagenesis was carried out using QuickChange (Stratagene). The wild-type Orfl l* was used as the template for single mutation. For multiple mutations, the single or double mutant was used as the template. All mutations were confirmed by DNA sequencing. Mutant proteins were purified with the same protocol for the wild- type Orfl 1*.
  • Enzymatic activity assay Orf 11*/Dbv8 activity was determined by LC-MS.
  • the assay mix containing enzyme (10 ⁇ g) and corresponding substrates (1 mM acyl-CoAs, 1 mM Tei-pseudoaglycone or vancomycin) in buffer (50 mM Tris pH 8.0, 100 mM NaCl, 1 mM DTT) (total volume 150 ⁇ ) was incubated for 2 h at 25 °C. Each reaction mixture was centrifuged at 16,000g for 5 min (Heraeus Biofuge Pico) and filtered on an ultracentrifugal filter unit (5 kDa cut-off membrane, Millipore) at due course.
  • buffer 50 mM Tris pH 8.0, 100 mM NaCl, 1 mM DTT
  • the filtrate was directly subjected to HPLC-ESTLTQ (Agilent 1200 Series interfaced with an ESI source coupled to a Thermo-Finnigan LTQ-XL ion trap spectrometer), using a gradient of 0-60% acetonitrile in 0.1% TFA in water over 30 min. Online LC-MS spectra were recorded by Xcalibur (Thermo Fisher Scientific, Inc.).
  • Crystallization and data collection The purified proteins were crystallized using the hanging drop vapor-diffusion method.
  • pyramidal crystals were obtained in a solution containing: 0.1 M Tris pH 7.5, 2.5 M NaCl.
  • Orfl l *-decanoyl- CoA hexagonal crystals were obtained in a solution containing: 0.1 mM MES pH6.5, 0.2 M ammonium sulphate, 30% (V/V) PEG 5000 MME and 1 mM decanoyl-CoA.
  • Dbv8-decanoyl-CoA crystals were obtained in a solution containing: 0.1 M sodium cacodylate pH 6.5, 0.2 M sodium acetate, 30% (V/V) PEG 8000 and 2 mM decanoyl- CoA.
  • Orfl l*-OBG-CoA crystals were obtained in a solution containing: 0.1 M Tris pH 8.5, 1.4 M ammonium tartrate, 1 mM CoA and 1 mM OBG.
  • the protein crystals were transferred to the cryoprotectant solution containing glycerol (20%, v/v) prior to the x-ray diffraction experiment.
  • X-ray diffraction data sets were collected on an ADSC Quantum- 315 or Quantum-210 CCD detectors at beamlines 13B1 and 13C1 of the National Synchrotron Radiation Research Center (Taiwan) and beamlines 12B2 and 44XU of Spring-8 (Japan). Data were indexed and scaled with the HKL2000 package 1 .
  • the redundancy independent merging R factor (R r. i .m ) and the precision indicating merging R factor (R p. i .m. ) were calculated using the program RMERGE.
  • the contents of asymmetric units were estimated from the Matthews coefficient .
  • the initial phase was determined by the single wavelength anomalous dispersion method.
  • the anomalous diffraction data were collected by selenium labeled Orf 11*.
  • the single wavelength anomalous dispersion (SAD) method was used to obtain phase information, and CRANK was used to find the phase solution.
  • Other native structures were solved by the molecular replacement method using the Se-Orf 11* as the search model.
  • the CRANK pipeline started with substructure detection and ended with model building, including procedures of substructure detection by AFRO/CRUNCH2 4 , substructure refinement by BP3 5 , Hand determination and density modification by SOLOMEN, and model building by BUCCANEER. Phase extension yielded electron density maps into which a polypeptide model was built with the program COOT.
  • the model was further refined with REFMAC. Figures were generated using PyMO. Detailed refinement statistics are given in Table 1.
  • Oligomerization states of the proteins in solution were determined by gel filtration chromatography and analytical ultracentrifugation (AUC). Substrate-enzyme affinity was determined using isothermal titration calorimetry (ITC). Biological assays were performed according standard protocols.
  • CoA/decanoylperoxide (4MFT), Orfl l*H196A/sulfenyl-CoA/decanoic acid (4MFW), Orfl l*H196A/sulfurperoxide-CoA/decanoic acid (4MFX), Orfl l*/CoA- disulfide/decanoic acid (4MFY), Dbv8/decanoyl-CoA (4MFZ), Orfl l*/octyl peroxide- CoA (4MG0), Orfl l*/octyl peroxide-Co A/glucose (4MG1).
  • the GNAT domain in Orf 11 */Dbv8 differs from the canonical GNAT fold as it lacks the first ⁇ strand, and the C-terminus extends with four additional helices (cclO- ccl3).
  • ⁇ -Strands ⁇ 3 and ⁇ 4 splay apart at C-termini, where Prol98 replaces a typical ⁇ -bulge.
  • the decanoyl-CoA bends in an 'S' shape edging in the splayed fingers ⁇ 3 and ⁇ 4 ( Figure 8).
  • the pantethine moiety is mediated by the loop ⁇ 3- ⁇ 9; the phosphate groups of 3' ,5'-phosphoadenosine are adjacent to the main chain atoms of the C-terminal helices (ccl0-ccl3), where the loop ccl0-ccl 1 may function as a P-loop makeshift.
  • the ribose is in a 2'endo-conformation as commonly observed in acetyltransferase co-crystal structures (Vetting, M. W. et al.
  • the decanoyl moiety uniquely extends into a deep- wide tunnel moulded by ⁇ 4, ccl 1, and the loop ⁇ 4- ⁇ 10 (Fig 2d).
  • the acyl moiety can be as lengthy or bulky as palmitoyl, naphthaleneacetyl or biphenylacetyl (Table 2), making Orfl l*/Dbv8 an adaptable enzyme able to generate new glycopeptide analogs.
  • ITC Isothermal titration calorimetry
  • the overall 10 A displacement may shape a closed active conformation in the domain junction to form the Tei pseudoaglycone binding site ( Figure 2e).
  • Figure 2e Tei pseudoaglycone binding site
  • ternary structures in complex with both decanoyl-CoA and Tei pseudoaglycone were attempted.
  • the ternary crystals were successfully obtained only through soaking the decanoyl-CoA-complexed H196A mutant crystals with Tei pseudoaglycone 3, suggesting the closed conformation is necessary for the pseudoaglycone binding (Figure 2g).
  • the all-helix domain is composed of eight helices (ccl-cc8) with two helix-turn-helix motifs in tandem (ccl-cc4), spooling a perpendicular 4-helix bromodomain-like central core (cc5- cc8) (residues 175-324, the Orfl l* numbering system is referred to unless otherwise stated), a reminiscence of eukaryotic histone
  • HAT acetyltransferase complexes.
  • Helices cc5 and cc6 juxtapose parallelly while connected transversely by a long loop (residues 84-100), in contrast to the antiparallel arrangement of helices cc7 and cc8.
  • the GNAT-like domain has a central 5 ⁇ -strand core ( ⁇ 1- ⁇ 5) flanked by two a helices, one short (cc9) and one fragmented long helix (the latter is composed of four and six short helices for Orfl 1* and Dbv8, respectively), on each side.
  • Orf 11*/Dbv8 is structurally akin to the AAA+ protein family (ATPases associated with diverse cellular activities) (supplementary Figure 2) 13 , whereas based on the functional consideration Orf 11*/Dbv8 may look more like a miniature of CBP/p300 in the HAT protein family.
  • the CBP/p300 houses a large GNAT domain alongside several smaller domains, including helix-turn-helix and bromodomain for recruiting acetylated lysine residues in histones.
  • the bromo-like domain in Orf 11*/Dbv8 may likewise act to recognize the peptide substrate Tei/A40926 pseudoaglycone.
  • Orfl l*/Dbv8 may represent a new architecture in the prokaryotic NAT enzyme family.
  • the GNAT domain in Orf 11*/Dbv8 differs from the canonical GNAT fold as it lacks the first ⁇ strand, and the C-terminus extends with four additional helices (cclO- ccl3).
  • ⁇ -Strands ⁇ 3 and ⁇ 4 splay apart at C-termini, where Prol98 replaces a typical ⁇ -bulge 9"11 .
  • the decanoyl- Co A bends in an 'S' shape edging in the splayed fingers ⁇ 3 and ⁇ 4 ( Figure 8).
  • the pantethine moiety is mediated by the loop ⁇ 3- ⁇ 9; the phosphate groups of 3 ' ,5'- phosphoadenosine are adjacent to the main chain atoms of the C-terminal helices (cclO- ccl3), where the loop cclO-Ccl l may function as a P-loop makeshift (Verstraeten, N., Fauvart, M., Versees, W. & Michiels, J. The universally conserved prokaryotic GTPases. Microbiol Mol Biol Rev 75, 507-542, second and third pages of table of contents, doi: 10.1128/MMBR.00009- l l (2011)).
  • the ribose is in a 2'endo-conformation as commonly observed in acetyltransferase co-crystal structures (Vetting, M. W. et al.
  • the decanoyl moiety uniquely extends into a deep- wide tunnel moulded by ⁇ 4, ccl 1, and the loop ⁇ 4- ⁇ 10 (Fig 2d).
  • the acyl moiety can be as lengthy or bulky as palmitoyl, naphthaleneacetyl or biphenylacetyl (Table 2), making Orfl l*/Dbv8 an adaptable enzyme able to generate new glycopeptide analogs.
  • ITC Isothermal titration calorimetry
  • the overall 10 A displacement may shape a closed active conformation in the domain junction to form the Tei pseudoaglycone binding site ( Figure 2e).
  • Figure 2e To locate the accurate Tei pseudoaglycone-binding site, ternary structures in complex with both decanoyl-CoA and Tei pseudoaglycone were attempted. The ternary crystals were successfully obtained only through soaking the decanoyl-CoA-complexed H196A mutant crystals with Tei pseudoaglycone 3, suggesting the closed conformation is necessary for the pseudoaglycone binding (Figure 2g).
  • acyltransfer can proceed through direct transfer or an acyl-enzyme intermediate as seen in histone ATs (Vetting, M. W. et al. Structure and functions of the GNAT superfamily of acetyltransf erases. Arch Biochem Biophys 433, 212-226, doi: 10.1016/j.abb.2004.09.003 (2005); Marmorstein, R. & Roth, S. Y. Histone acetyltransferases: function, structure, and catalysis. Curr Opin Genet Dev 11, 155-161 (2001)).
  • vancomycin (Van) 6 (with a vancosamine-glucose disaccharide on 4Hpg) was
  • acyl-NAC can be an acyl- CoA surrogate (Fig 4a,b, trace ix).
  • the reaction efficiency was improved if free CoA was added.
  • acyl group is transferred from acyl-NAC to the free CoA through the transesterification reaction in the active site, whereof CoA turns its role from a substrate ligand to a cofactor.
  • An enzyme-catalyzed acyl-swapping reaction was serendipitously discovered, as Tei 1 was converted to octyl- substituted Tei (Cg-Tei) 9 in an enzymatic reaction added with both Tei 1 and octyl-CoA 10 (Fig 4a,b, trace xi).
  • Vancomycin versus Teicoplanin Systematic Review and Meta- Analysis. Antimicrob Agents Ch 53, 4069-4079, doi:Doi 10.1128/Aac.00341-09 (2009)).
  • CoA-disulfide 12 is generated considerably in the Orfl l*/Dbv8 catalytic reactions ( Figures 4a,b, traces vii, viii). This oddness prompted revisiting the decanoyl-CoA-containing binary structures from collated data sets to glean clues on this oxidation proclivity.
  • a ternary structure in complex with decanoic acid and CoA was first observed, wherein the thioester scissile bond is broken suggesting that acyl-CoA can undergo a hydrolysis half reaction without presence of Tei pseudoaglycone 3 ( Figure 3c).
  • CoA-disulfide was also found in a second structure (Fig 5a), suggesting that the enzyme in a way fosters sulfhydryl oxidation of CoA.
  • a decanoyl peroxide- sulfane species 16 was identified in a structure (Figure 5f). The formation of the product hinted the origin of decanoylperoxide 15. Albeit other routes, such as the radical mechanism, are possible, it was proposed that 0 2 likely reacts with the soft sulphur atom of acyl-CoA to form a peroxide- sulfonium anion, which attacks the carbonyl carbon of the acyl moiety and then rearranges into the decanoyl peroxide- sulfane species 16 (Figure 5g).
  • the reactive superoxide/sulfenyl-CoA can be formed in the enzyme, further examined was the reaction in the presence of CoA 5 and ⁇ -octyl glucoside ( ⁇ - OG) 17, an N-acyl glucosamine mimic with an alkyl ether linkage to the anomeric carbon of glucose. Since the peroxide/sulfenyl products are too unstable to detect, we also took advantage of x-ray crystallography in a hope to snapshot possible ligand-complexed structures.
  • the preliminary ED50 (potency) of the 2-decanoyl,6-octanoyl teicoplanin analog was determined as follows. 6-8 weeks BALB/c female mice were purchased from the National Laboratory Animal Breeding and Research Center, Taipei, Taiwan. Mice with average body weight of 25 to 30 g were subjected to infection via intraperitoneal (i.p.)
  • mice were randomly assigned into five groups at the start of the experiment and administered different amount of either vancomycin, teicoplanin, 2-C 1o -6-C 8 -Teicoplanin, or saline (as a blank control) by i.v. twice a day for two days (from day 1 to day 2, a total of 4 doses).
  • the ED 5q was determine by the concentration of compounds sufficient to rescue 50% infected mice. The results are shown in the table below:
  • the MIC values were determined by the broth microdilution method, as recommended by the National Committee for Clinical Laboratory Standards (NCCLS). Briefly, overnight cultures of tested bacteria were suspended to a turbidity of 0.1 OD units (1-5x10 CFU/ml). Micro titer plates containing serial dilutions of each
  • antimicrobial agent (0, 1, 2, 4, 8, 16, 32, 64, and 128 ⁇ g/ml) were inoculated with each organism to yield the appropriate density (l ⁇ 5xl0 5 CFU/ml) in a 200 ⁇ L final volume. The plates were incubated for 18-22 h at 37°C. The MIC for all isolates was defined as the lowest concentration of antimicrobial agent that completely inhibited the growth of the organism, as detected with an unaided eye (Figure 26).
  • ATCC 29302/ ATCC 33186 a standard strain
  • ATCC 51299 a low-level vancomycin-resistant (VanB type)
  • ATCC 51559 a multidrug-resistant strain (ampicillin, ciprofloxacin, gentamicin, rifampin, teicoplanin and vancomycin, VanA type VRE)
  • ATCC 700221 a strain resistant to vancomycin, VanA type VRE.
  • ATCC 700802 is a strain resistant to gentamicins and vancomycin. The results are shown in the table below:
  • Cowtan, K The Buccaneer software for automated model building. 1. Tracing protein chains. Acta Crystallogr D 62, 1002-1011, doi:Doi

Abstract

L'invention concerne des composés de formule (I), ou des sels pharmaceutiquement acceptables desdits composés, et des compositions pharmaceutiques les contenant. Les composés selon la présente invention sont utiles pour inhiber la croissance bactérienne. Des procédés d'utilisation desdits composés pour traiter et/ou prévenir une infection bactérienne ainsi que des procédés de préparation de ces composés sont également décrits.
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EP0306645A2 (fr) * 1987-09-07 1989-03-15 Gruppo Lepetit S.P.A. Dérivés ressemblant à la teicoplanine
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